The present invention relates to novel compounds derived from N-(benzenesulfonyl)-(L)-proline, to the process for their preparation and to their use in therapeutics.
These novel compounds have an antagonistic action towards bradykinin and are useful in therapeutics, particularly for the treatment of pain and inflammation and especially for the treatment of asthma, cerebral traumatic shock and allergic rhinitis.
It is known that one of the possible treatments for certain pathological conditions of a painful and/or inflammatory nature (such as asthma, rhinitis, septic shock, toothache, etc.) is to inhibit the action of certain hormones such as bradykinin or kallidin. These peptide hormones are in fact involved in a large number of physiological processes, some of which are closely associated with these pathological conditions.
Although no product possessing this mode of action has yet been marketed, numerous studies have been undertaken in order to understand the mode of action of kinins, particularly bradykinin and its homologs, and then create compounds capable of antagonizing the bradykinin receptors. Pharmacological Reviews, vol. 44, no. 1, pages 1-80 (1992) and Biopolymers (Peptide Science), vol. 37, pages 143-155 (1995) may be mentioned among the numerous publications relating to this work.
Bradykinin is a peptide hormone consisting of 9 amino acids (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) and kallidin is a peptide hormone (Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) which contains an additional amino acid (Lys) compared with bradykinin. It is known that earlier studies made it possible to obtain peptides which interact with the bradykinin receptors: some of them, like bradycor (CP.0127 from Cortech), icatibant (HOE 140 from Hoechst) [xe2x80x9cbradycorxe2x80x9d and xe2x80x9cicatibantxe2x80x9d are international non-proprietary names (INN)] or NPC 17761 (from Scios-Nova), have an inhibitory action on the binding of bradykinin to its B2 receptor. Recent publications refer to other peptides capable of having an antagonistic action on bradykinin in respect of its B2 receptor; examples of these publications which may be mentioned are WO-A-97/09347, WO-A-97/09346, U.S. Pat. No. 5,610,140, U.S. Pat. No. 5,620,958, U.S. Pat. No. 5,610,142 and U.S. Pat. No. 5,597,803. Furthermore, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B2 receptor, especially in EP-A-0596406, EP-A-0622361, U.S. Pat. No. 5,578,601, FR-A-2735128, JP-A-09 040662, FR-A-2737892 and WO-A-97/11069. It is also known that certain compounds whose structure is more or less related to those of the compounds referred to in the present patent application have already been described for their possible antithrombotic properties, especially in the publications DE-A-3617183 and EP-A-0261539.
There is a need for reducing or eliminating pain and inflammation in mammals and particularly in man.
To meet this need, a novel technical solution has been sought which is effective in the treatment of pain, irrespective of its origin, and especially in the treatment of pain associated with inflammatory phenomena or traumatisms.
According to the invention, it is proposed to provide a novel technical solution which involves competitive binding, at the bradykinin B2 receptor, between (i) bradykinin and related or analogous hormones, and (ii) an antagonist, and utilizes compounds of the benzenesulfonamide type which are structurally different from the known products mentioned above and which are capable of limiting or substantially inhibiting the binding of bradykinin and analogous hormones to said bradykinin B2 receptor.
According to this technical solution, the novel compounds bind competitively to the bradykinin B2 receptor without causing the effects of bradykinin on this receptor (these novel compounds are said to be antagonists). This results in the appearance of a state analogous to that observed in the absence of bradykinin, namely a reduction in pain and in inflammatory reactions.
In accordance with this novel technical solution, it is proposed according to a first aspect of the invention to provide compounds derived from N-(benzenesulfonyl)-(L)-proline as novel industrial products, according to a second aspect of the invention to provide a process for the preparation of these compounds, and according to a third aspect of the invention to provide the use of these compounds, especially in therapeutics, as analgesics and/or anti-inflammatories.
In accordance with the novel technical solution of the invention, an N-(benzenesulfonyl)-L-proline compound is recommended as a novel industrial product, said compound being selected from the group consisting of:
(i) the compounds of formula I: 
in which:
X is a halogen atom,
A is a divalent group
xe2x80x94NHxe2x80x94(CH2)nxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94NHxe2x80x94CH2xe2x80x94 or

Q is a group 
R1 is a hydrogen atom, a halogen atom, a C1-C3, alkyl group with a linear or branched hydrocarbon chain, or a C1-C5 1-oxoalkyl group,
R2 is a hydrogen atom or an OH group, and
n is 2, 3 or 4; and
(ii) their addition salts.
According to the invention, a process for the preparation of the compounds of formula I and their addition salts is also recommended.
The use of a substance which antagonizes a receptor of bradykinin and analogous hormones is also recommended, wherein a bradykinin B2 receptor antagonist selected from the compounds of formula I and their non-toxic addition salts is used for obtaining a drug intended for use in therapeutics to combat pathological conditions involving bradykinin or its analogs, in particular to combat pain, and especially in the treatment or prevention of pathological conditions associated with inflammatory or painful states.